Emerging technologies approach complex eye disease from new directions

Many concepts are in the pipeline, but technologies for long-term delivery of drugs into the anterior segment are lacking. For posterior disorders, however, drug-eluting implants have been FDA approved and more are on the way.

Glaucoma specialists in particular seek drug-eluting devices largely because of patient noncompliance with dosing instructions, according to Steven D. Vold, MD.

Topical medication is a major issue, especially in the glaucoma field because long-term self-administration of eye drops is needed to prevent potential blindness, he said, citing one study that found only a 50% to 60% refill rate for latanoprost eye drops.

“That means that close to half of our patients are really not getting in their medicines on a regular basis, even if it is one drop a day,” Vold said. “If we can somehow find a way to improve control of the glaucoma or treat inflammatory diseases with steroid medications without patients having to put in drops, then that really is a big deal.”

Peter A. Campochiaro, MD, said drug-eluting implants may mitigate the treatment burden for patients with age-related macular degeneration as well.

“Current treatments for neovascular AMD, for macular edema, require frequent intraocular injections. That is a significant burden on patients, their families and physicians,” Campochiaro said. “If there was a means to sustain treatment effect after a single injection and reduce the burden of injections, that would be a major benefit to patients.”

Drug delivery technologies

Sustained drug delivery technologies such as intravitreal implants, punctal plugs, contact lenses, IOLs and nanoparticles in development will enable clinicians to optimize treatment safety and efficacy, according to proponents.

The efficacy of drug-eluting implants hinges on implant size and drug potency, Campochiaro said.

“One of the challenges for sustained deliveries in the eye is that the implant has to be relatively small. So, the amount of drug that you can load into an implant is relatively small,” he said. “You need very potent drugs in order for that to work very well. Steroids are extremely potent, and they also lend themselves well to incorporation into polymers.”

Barbara Wirostko, MD, discussed the need for delivery of large proteins into the posterior segment.

“I think we still need to tackle the problem of how we want to deliver proteins, in particular large molecules such as anti-VEGF therapies to the posterior segment,” Wirostko said. “There’s a huge unmet need and a huge value for whoever can tackle that. Obviously, from a medical perspective, there is also a clear unmet need to deliver drugs for sustained periods of time in our glaucoma patients because of all the challenges of delivering topical eye drops chronically.”

Lisa Schopf, PhD, of Kala Pharmaceuticals, said the company is developing a novel noninvasive drug delivery technology that facilitates penetration through mucus to enhance delivery of drugs to mucus-protected tissues such as the eye.

“In many ways, I think the message is simple: The technology allows penetration through a barrier that would otherwise trap and clear away drugs very quickly,” Schopf said. “This results in enhanced tissue exposure, and that’s a huge, distinct advantage.”

The path to treating complex and changing eye diseases may lie in developing a “whole new set” of miniaturized devices that provide programmable drug delivery, according to Mark S. Humayun, MD, PhD. Humayun designed the Argus II retinal prosthesis system (Second Sight), which is FDA approved. He and his colleagues have been working on another implantable bioelectronics device, the Posterior MicroPump (Replenish).

“In the future, the eye won’t be a place where you can only put in a plastic intraocular lens or an eluting drug delivery platform, but ophthalmologists might also have the opportunity to put in bioelectronics drug delivery implants that are programmable, therefore allowing personalized dosing of pharmaceuticals, as well as the ability to refill the pump in the clinic,” Humayun said.

Existing implants

Two drug delivery devices currently are approved by the FDA for diseases of the retina and vitreous: Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb) and Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan).

Retisert is approved for noninfectious uveitis, and Ozurdex is approved for macular edema associated with branch or central retinal vein occlusion as well as noninfectious uveitis. Ozurdex, a bioerodible system that provides dexamethasone for approximately 3 months, has been examined in two phase 3 studies that showed both the 350-µg and 700-µg dose to be superior to sham treatment in patients with diabetic macular edema.

“This may become one of the additional drugs that we have in our armamentarium for the treatment of diabetic macular edema,” David S. Boyer, MD, said.

The slow release of dexamethasone does not pose a systemic safety problem, and patients receive injections less often, which also plays a role in safety, Boyer said. However, steroids have a downside.

“The problem is that steroids have potential disadvantages; that is, they cause cataracts and they cause increase in intraocular pressure,” Boyer said. Disease management becomes difficult when a patient responds to a long-duration implant with increased IOP, he said.

Another implant, Iluvien (fluocinolone acetonide, Alimera Sciences), has CE mark approval in the European Union. In March, Alimera resubmitted a new drug application for Iluvien to the FDA. The low-dose fluocinolone implant can last up to 3 years and is especially helpful in patients with chronic macular edema associated with diabetes, which can have a large inflammatory component, Boyer said.

New implants and plugs

Drug delivery devices in development include the Durasert glaucoma implant (pSivida), prostaglandin analogue punctum plugs (Ocular Therapeutix), punctal plug delivery system (QLT), Ophthalmic MicroPump System, L-PPDS latanoprost punctal plug delivery system (Mati Therapeutics), Vision5 ocular drug delivery system (ForSight Labs), and ranibizumab drug port delivery system (Genentech).

Vold said that he has used three implants: the QLT punctal plug, the Ocular Therapeutix punctal plug and the Vision5 system.

The QLT device delivers latanoprost from a drug-eluting core over 3 months. However, there are challenges, Vold said. The device’s unwieldy size makes it difficult to insert, and the implant can potentially fall out or erode through the punctum.

“We had good results with this, but I can tell you that they’re not particularly easy to put in,” Vold said.

The Ocular Therapeutix plug includes a light source visualization aid to monitor retention over the treatment period.

“It’s a clever system,” Vold said. The visualization aid expands inside the plug, and the light source can be used to verify that the plug is in good position, initially and at subsequent patient examinations.

The Vision5 system also shows promise, Vold said. He described the system as a small scleral ring impregnated with therapeutic agent.

The MicroPump uses electrolysis to deliver drug in a controlled manner out of a tiny reservoir and into the eye for intravitreal drug delivery. Vold said the pump system is versatile and durable, storing a 3- to 9-month volume of drug molecule or biologic in a minimally invasive implant that is embedded using the same surgical procedures as used to implant glaucoma setons. However, Vold expressed uncertainty about potential risks associated with the pump, such as device erosion and infection.

“It’s the world’s smallest [bioelectronic] pump to deliver drugs into the eye, and it is refillable in the clinic,” Humayun said, adding that drug is delivered correctly and accurately via metered doses in nanoliter units.

Humayun and colleagues conducted a phase 1 study of the MicroPump at the Puerto de Herrera Clinic in Guadalajara, Mexico, to show that the device could be tolerated in the eye.

“It could dose as programmed. The eye tolerated the device very well,” Humayun said. “There weren’t any obvious issues that we had overlooked in our preclinical tests.”

Further clinical study in the United States is planned. The pump is “ready to go,” Humayun said, with the next steps in the road to market being subject to business decisions.

Future versions of the MicroPump technology would adapt well to glaucoma treatment because it can deliver drug and monitor pressure in a closed loop, akin to insulin pumps measuring glucose, Humayun said. Future versions could also hold more than one type of drug in different reservoirs, avoiding mixing them.

“Having a device that can deliver therapeutic drugs when your pressure goes up or breaks through a certain desired level (ie, treat you on demand) could be a game-changer,” he said.

Another reservoir-based delivery system in development is the ranibizumab drug port delivery system. The implant device would allow slow diffusion of ranibizumab into the eye and provide low constant levels of the drug for prolonged periods, Campochiaro said. However, implantation would require surgery.

“Whenever you go to the operating room, that’s a little bit of an impediment,” Campochiaro said.

The procedure would require making an opening in the sclera, inserting the small reservoir and covering it with conjunctiva. Repeated injections could be made through a diaphragm on the device.

The Durasert implant, placed into the subconjunctival space, delivers sustained-release latanoprost for glaucoma and ocular hypertension. It is undergoing phase 1/2 clinical trials in the U.S.

The L-PPDS latanoprost punctal plug delivery system is undergoing a phase 2 trial.

Nanoparticles as drug vehicles

Nanotechnology is being applied to various drug delivery concepts such as drug-carrying particles.

“Nanoparticles provide a way to incorporate drugs that can be injected through a small-gauge needle, but there’s not real good proof of concept yet. There are good experiments in animals, but we don’t know yet how well they’re going to be tolerated, how long they can provide drugs — all of those important questions in humans,” Campochiaro said.

Wirostko is co-founder and chief scientific officer for Jade Therapeutics, which is developing a topical drug-eluting therapy for corneal diseases such as bacterial ulcers, non-healing corneal defects, epithelial defects and corneal neovascularization. The therapy is based on a unique proprietary polymer composed of a cross-linked modified hyaluronic acid.

“The approach enables sustained drug delivery of both small molecules and proteins from a novel proprietary cross-linked hyaluronic acid,” Wirostko said. “Our initial focus is on corneal diseases of unmet need. It’s basically a gel that’s made into a film. It’s the film that will be applied topically against the conjunctiva underneath the eye lid or in the inferior cul-de-sac. You could also inject this polymer as a liquid that in turn becomes a gel within 20 minutes, thus occupying and conforming to various ocular cavities. It’s very versatile.”

The polymer cross-links to a skeletal matrix that incorporates drugs, proteins and even cells, Wirostko said.

The technology is in the preclinical stage, and clinical trials are expected to commence by 2016, as the polymer has already been in humans to deliver cells intradermally, she said.

“The SKS Ocular technology revolves around the ability to manufacture particles reliably,” Wirostko said.

The SKS team is focusing on the development of microparticles and nanoparticles that can deliver both large and small molecules for retinal diseases and glaucoma.

“So, whether it’s large or small particles, the novelty is around the technology, their method of manufacturing with any shape being possible. It enables custom-tailor release characteristics, the use of any polymer and can reliably place biologics into the polymer.”

Neurotech is developing an implant that elutes anti-VEGF to treat exudative AMD.

“This drug will emit, for 7 years, levels that are hopefully high enough to prevent the growth of choroidal neovascularization,” Boyer said. “There are certainly biologic effects of having this implant placed, and some of the [early] patients did extremely well. It is an extremely promising long-term treatment for wet macular degeneration and hopefully other conditions that require chronic VEGF suppression, such as some types of vein occlusions in diabetes.”

Campochiaro is helping to develop a polymer-drug biomolecular conjugate (GrayBug) for the treatment of wet AMD and other neovascular diseases. The technology allows sustained drug delivery into various regions of the eye while minimizing inflammation associated with controlled-release technologies, according to the company website.

Envisia’s PRINT particle technology is in preclinical testing for glaucoma and the lead optimization phase for AMD. The biodegradable PRINT particles are designed to deliver sustained doses of prostaglandin analogue.

“They use novel nanoparticle technology and are combining that with the drug to inject into the eye and have a lot of promise,” Humayun said.

Mucus penetration

Kala Pharmaceuticals recently developed mucus penetrating particle (MPP) technology for ocular drug delivery, which involves the use of surface-modified muco-inert nanoparticles to deliver drugs through mucosal tissues.

In December 2013, Kala submitted an investigational new drug application to the FDA to begin a phase 3 clinical trial of its MPP-formulated loteprednol etabonate ophthalmic nano-suspension for treatment of postoperative inflammation and pain after cataract surgery. The trial is designed to show an anti-inflammatory effect similar to that of other steroid-based treatments with less frequent dosing.

“Preclinically, we have demonstrated that the mucus-penetrating particles diffuse through mucus,” Schopf said. “Using fluorescently labeled nanoparticles administered to animals, we have shown a nice, even distribution in a variety of mucosal tissues and specifically in the eye. We have also demonstrated that this enhanced mucus penetration may facilitate delivery of drugs to the back of the eye following topical administration, and this has become a major focus for the company.”

The MPP technology relies not only on nanoparticle size but also the surface coating, Schopf said.

“I think most nanoparticles up to this point may be the right size, but many of them actually adhere to mucus and are cleared from the eye very rapidly,” she said. “The huge advantage of MPP is its muco-inert surface, which allows the nanoparticles to diffuse through mucus and provide much greater penetration into mucus-protected tissues.”

Kala’s MPP system is applied to the eye as a liquid suspension without the need for a needle.

“It’s a nano-suspension, so there’s no viscous gel or cream,” Schopf said. “That’s another advantage. The consistency of the MPP nano-suspension is very similar to that of water, and it’s not a heavy ointment or gel that you’re putting in your eye.”

Contact lenses

In a study, researchers combined glaucoma medication with nanodiamonds and embedded them onto contact lenses. The drug was then released into the eye when it encountered the patient’s natural tears.

According to the study published in ACS Nano, the new technology proved promising for sustained glaucoma treatment. Investigators said the mode of drug delivery — exposure to tears — may prevent premature drug release when the lenses are in storage. They also noted that the nanodiamond-drug compound made the contact lenses more durable.

Contact lenses have upsides but also have shortcomings in terms of duration of effect and complications, Wirostko said.

“Contact lenses are very appealing,” she said. “But in terms of chronic treatments, I wouldn’t necessarily want to use contact lenses. I think a contact lens is great for short-term treatment, but for chronic long-term therapy, it’s a challenge. I think for things like bacterial ulcers, we don’t necessarily want to put a contact lens on early in the infectious process because it may actually be exacerbating it.” – by Matt Hasson